More than 80 autoimmune diseases have been identified. Autoimmune diseases are thought to affect 14-22 million people in the US and disproportionately affect women. These diseases impart a significant fiscal burden to the country's health care system. Although research has lead to significant new mechanistic insights for autoimmune diseases, the causes of the majority of these diseases remain unknown. The broad long-term objective of the proposed research is to understand the relationship between aberrant DNA repair and autoimmune disease. We have recently generated base excision repair compromised mice carrying the Y265C DNA polymerase beta variant, and found that they exhibit symptoms of autoimmune disease. In this application, we propose to perform experiments to quantitatively characterize the phenotypes of our mice in order to generate testable hypotheses, the outcomes of which have the potential to provide important mechanistic insight into the role of aberrant DNA repair in autoimmunity. The specific aims are to characterize mice expressing the Y265C base excision repair variant for the presence of autoimmune disease, to test the hypothesis that B and/or T cells are required for the manifestation of autoimmune disease in the Y265C mice, and to test the hypothesis that initiation of the repair of oxidative DNA damage is a prerequisite for autoimmune disease in the Y265C mouse model. To accomplish these goals we will quantitatively assess the symptoms of autoimmune disease in these mice, and their time to occurrence. We will also generate mice expressing the Y265C variant in a Rag1 deficient background and in a DNA repair glycosylase deficient background and assess disease symptoms and time to occurrence in order to determine if B and/or T-cells are required for disease and if oxidative DNA damage plays a role in autoimmune disease. The significance of our studies is highlighted by the fact that there are over 100 documented Single Nucleotide Polymorhisms (SNPs) in genes encoding enzymes that function in base excision repair. Thus, a combination of a germline SNP in the presence of oxidative metabolism could result in autoimmune disease. Furthermore, the mechanistic insights gained in our studies of aberrant DNA repair and autoimmunity are likely to lead to the development of novel therapies for autoimmune diseases. PUBLIC HEALTH RELEVANCE: The goal of this application is to determine the role(s) of aberrant DNA repair in autoimmune disease. This is important because the results have the potential to provide insights into how aberrant DNA repair leads to autoimmune disease and could result in new therapies for autoimmune disease.